Accès à l' Innovation Thérapeutique En Gastro-Entérologie - Dr Bernard AVOUAC Rhumatologue - SAHGEED
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Accès à l’ Innovation
Thérapeutique
En Gastro-Entérologie
Dr Bernard AVOUAC
Rhumatologue
Ancien président de la
Commission de la TransparenceLE DÉVELOPPEMENT DU MÉDICAMENT
Connaissance
de la maladie
Développement
Besoins du
Bénéfice
du patient patient
médicament
Identification d’une
cible biologiqueDécouverte et Développement
du Medicament
Lead Preclinical Clinical
Discovery HTS Optimization Evaluation PoC Full Development Registration
Product
differentiation
Target Target
identification progression Market
Target Molecule
validation progression access
Genetics
Genomics Combo chem Pharmacology Clinical Additional indications
Bioinformatics HTS Toxicology studies
(efficacy - safety) (efficacy - safety)
Pharmacogenetics
PharmacogenomicsPatient
Bénéfices Société
Industrie
Industrie
Risques Agences Reglementaires Coûts
Organismes Payeurs
Patient Industrie
Société
PatientOù est la juste balance?
R&D SOCIETE
Besoin
Risque Patient
Côut
Efficacité SécuritéEMA : procédures accélérées • L'AMM conditionnelle : valide seulement 1 an au lieu de 5 et nécessite de compléter l’évaluation • L'AMM pour circonstances exceptionnelles : lorsque le dossier d'évaluation du médicament n'est pas complet et qu’il existe un besoin thérapeutique • L'AMM accélérée : 150 jours au lieu de 210 jours en cas d’intérêt majeur du point de vue de la santé publique • L’Adaptive Pathways : procédure de mise à disposition précoce en cas de besoin non satisfait dans une sous- population avec poursuite du développement clinique
Mise à disposition avant AMM en France
• Les ATU dites nominatives
– Demandées par le médecin prescripteur au bénéfice d’un
patient nommément désigné
– Elles sont accordées si l’efficacité et la sécurité des
médicaments sont présumées favorables en l’état des
connaissances scientifiques
• Les ATU dites de cohorte
– Sollicitées par le laboratoire
– Elles sont accordées à des médicaments dont l’efficacité et la
sécurité sont fortement présumées par les résultats d’essais
cliniques en vue d’une demande d’AMM
– La demande d’AMM doit avoir été déposée ou l’entreprise
doit s’engager à la déposer dans un délai déterminéLA COMMISSION DE LA TRANSPARENCE (CT)
La CT évalue les médicaments et émet un avis sur leur prise en charge par
la Sécurité sociale et/ou leur utilisation à l’hôpital
Jugement sur l’intérêt thérapeutique du produit, par indication
thérapeutique :
Service Médical Amélioration du Par comparaison
Dans l’absolu Service Médical
Rendu
Rendu
aux alternatives
thérapeutique déjà
SMR existantes
ASMR
Place dans la
stratégie Population cible
thérapeutiqueLE SMR ET L’ASMR
Critères d’évaluation :
• Efficacité et effets indésirables;
• Place dans la stratégie thérapeutique
SMR •
•
Gravité de la pathologie
Caractère préventif, curatif ou symptomatique
= valeur intrinsèque du produit • Intérêt de santé publique
4 niveaux de SMR :
Important, modéré, faible, insuffisant
Critères d’évaluation :
ASMR • Niveau de preuve apporté
• Pertinence des critères retenus
= progrès thérapeutique apporté • Quantité d’effet observée
• Par indication ou dans une Echelle graduée de 1 à 5 :
sous-population relevant de l’AMM I : Progrès thérapeutique majeur.
II : Amélioration importante
• Par rapport à un comparateur ou dans III : Amélioration modeste
le cadre d’une stratégie thérapeutique IV : Amélioration mineure
V : Absence d’amélioration avec avis favorable à l’inscriptionInflammatory Bowel Disease
Disease Background and Treatment Paradigm
Background
Inflammatory Bowel Disease is an umbrella term for disorders causing chronic inflammation of the intestinal tract
and includes Crohn’s disease and ulcerative colitis.
Crohn’s Disease Ulcerative Colitis
Inflammation of the lining of the digestive tract (may Inflammation and sores in the colon (large intestine)
affect any part of the GI tract) and rectum
~780,000 individuals affected in the US ~900,000 individuals affected in the US
~1.1 million individuals affected in the EU ~1.5 million individuals affected in the EU
Treatment Paradigm
First Line Second Line Third Line
Anti-TNFs
Corticosteroids (Remicade, Humira,
Simponi*)
Immuno-
Surgery
modulators
5-ASAs Other biologics
(Entyvio, Stelara*)
Source: Insight Strategy Advisors; *Simponi only indicated for UC, Stelara only indicated for CD.bowel disease affecting all parts of
MALADIE DE CROHN
gastrointestinal tract - from mouth to
anus
Normal Colon vs. Crohn’s Disease Colon
• Crohn’s Disease (CD) is a relapsing and remitting
autoimmune disorder where disease exacerbations
are followed by periods of remission
• CD is characterized by its location within the GI tract
– most commonly it affects the ileum, colon or both
• The disease is characterized by a range of symptoms,
5% most commonly including abdominal pain, diarrhea,
Anatomic Location
5% vomiting, fever and weight loss
• The exact cause of CD is unknown, although it is
35% thought to be due to a set of genetic, microbial and
20%
environmental factors
• There is no cure for CD, most patients (~70-80%) will
require surgery – and ~45% will require multiple
35%
surgeries – to correct issues such as strictures and
fistulae
Ileocolitis
Ileitis
Granulomatous colitisTraditional endpoint requirements for CD are evolving and
changing measures need to be acknowledged in new clinical trials
• Developed over 40 years ago, the CD Activity Index (CDAI)
historically is the “gold” standard requirement for measuring
disease activity in clinical trials
• However, mostly due to its complexity, the CDAI is seldom used
in clinical practice. It has also been recognized in recent years
that the CDAI has a number of limitations
CDAI
• The reliability and validity of the index have been questioned
because of:
- Inconsistency (physicians do not always follow formal scoring
SES-CD protocols in reporting symptoms) and some physician evaluations are
subjective
- Short-term perspective (only captures patient condition over recent
days)
PRO As a result..
• Regulatory bodies are considering replacing CDAI
with a combination of patient-reported outcomes
and endoscopy measurementsDisease activity and severity can vary over time given the
Mild Moderate Severe Fistulizing • CD severity is
• CDAI of 150-220
relapsing
• CDAI of 220-450
and remitting
• CDAI > 450
nature of the
• Presence of perianal
disease
determined at
or non-perianal diagnosis based
• Patients are • Patients have failed • Persistent symptoms fistulae
ambulatory, eating treatment for mild despite intensive on the physician’s
and drinking, without disease treatment • Considered to be a assessment of
dehydration; may sign of active disease patient’s
have tenderness, • Prominent symptoms • Cachexia (BMI < 18
mass, obstruction, or – fever, weight loss, kg m-2), or evidence • Medical treatment of symptoms
less than 10% weight abdominal pain and of obstruction or underlying active
loss tenderness, abscess disease is typically • Most patients
intermittent nausea consistent with have active
• 34% of diagnosed or vomiting, or • CRP increased treatment for severe
patients* anemia. CD disease at
• 32% of diagnosed diagnosis
• C-reactive protein patients*
(CRP) elevated above • As CD is a
the upper limit of
normal relapsing and
remitting disease,
• 34% of diagnosed
patients*
patients can
transition from
Disease severity spectrum one severity
Goal
category to
another
Remission depending on
• CDAI (approximate) ofmoderate-to-severe patients fail to respond and progress to
TREATMENT PATHWAY
Mild Moderate Severe Fistulizing
IV corticosteroids +
Oral 5-ASA or oral Oral corticosteroids, with initiate
budesonide or without oral 5-ASA immunosuppressants + Antibiotics Surgery
consider parenteral
nutrition
IV corticosteroids +
Maintenance 5- initiate Maintenance Maintenance
ASA or drug Other oral Maintenance 5-
corticosteroids ASA imminosuppressants + immunosuppressa TNF-α inhibitor immunosuppressa
holiday consider parenteral nts nts
nutrition
Maintenance Maintance TNF-α
Maintenance 5- Treat as Moderate Try another TNF-α
immunosuppressa TNF- α inhibitor inhibitor +/-
ASA disease inhibitor
nts immunosuppressa
nts
• Fistulizing disease is not considered in
classifications of mild, moderate, and severe
Legend
disease outlined in existing treatment
Classification at Maintenance TNF- Try another TNF-α
guidelines α inhibitor +/-
diagnosis inhibitor or
immunosuppressa
1st line Entyvio
treatment • But because fistulas often require surgery nts
2nd line and treatment with TNF-α inhibitors, they
treatment
3rd line are often considered consistent with severe, Maintenance TNF-α
treatment active disease in clinical practice inhibitor +/- Surgery
4th line immunosuppressants, or
treatment maintenance Entyvio
5th line • Patients who are non- responsive to steroids
treatment and have flares are likely to try multiple TNF-
α inhibitors or EntyvioCompetitive Landscape: Pipeline
ORAL INJECTABLE INJECTABLE CROHN’S DISEASE PIPELINE
BIOSIMILAR FRA
PIPELINE PRODUCTS*
CURRENTLY MARKETED BIOLOGICS 2018 2019 2020 2021 2022 2023 2024
upadacitinib
(JAK1)
adalimumab adalimumab filgotinib ozanimod etrolizumab ustekinumab
vedolizumab infliximab
CROHN’S DISEASE
(anti-TNF) biosimilar (adalimumab biosimilar (JAK1) (S1P1) (b7) biosimilar
(IL-12/23)
biosimilar) (anti-TNF)
ustekinum
infliximab infliximab (adalimuma risankizumab
(anti-TNF) ab (IL-23) Biomarker-driven therapy
(IL-12/23) biosimilar b biosimilar) targeting patients with
elevated ITGAE expression
guselkumab
(IL-23)
• HUMIRA (adalimumab) biosimilars are expected to launch in 2018 in FRA; REMICADE (infliximab) biosimilars (INFLECTRA, REMSIMA)
have already launched and represent 40% of biologic market share across indications
• Etrolizumab is a biomarker-driven biologic, which is expected to launch from 2023
• STELARA (ustekinumab) biosimilars are expected in 2024
* NOTE: Estimated based on projected launch dates from secondary research. BI: Boehringer Ingelheim; IL: interleukin; ITGAE: integrin αE Source: CBP secondary research
gene; JAK: Janus kinase; PDE: phosphodiesterase; S1P1: sphingosine-1-phosphate receptor 1; TNF: tumor necrosis factor.FRA Competitive Landscape Stimulus:
Treatment Algorithm
TREATMENT ALGORITHM
CROHN’S DISEASE
CURRENT ALGORITHM
Anti-inflammatory 5- Corticosteroid (e.g.
ASA prednisone) ALGORITHM IN 2027
Oral Immunomodulator Anti-
Corticosteroid (e.g.,
(e.g., TOFACITINIB, inflammatory
+/- prednisone)
Immunomodulator ozanimod) 5-ASA
(e.g., AZA, 6-MP, INFLIXIMAB ADALIMUMAB
tacrolimus) +/-
Biomarker-driven
Immuno-modulator
Anti-TNFs Biologic
(e.g., AZA, 6-MP)
+/- (e.g., etrolizumab)
Immunomodulator Other Biologics
(e.g., AZA, 6-MP, VEDOLIZUMAB,USTEKINUMAB
tacrolimus) Other Biologics (anti-
Immunomodulator
integrins,VEDOLIZUMAB,
(e.g., AZA, 6-MP)
interleukin inhibitors)
Surgery may be considered at any phase of treatment
based on patient severity and eligibility Surgery may be considered at any phase of treatment
based on patient severity and eligibilityRECTO COLITE ULCERO- HEMORRAGIQUE
TREATMENT ALGORITHM
UC TREATMENT PATHWAY
BIOLOGICS
MILD-TO-MODERATE MODERATE-TO-SEVERE
5-ASAs Immunomodulators
CONVENTIONAL
THERAPY
Corticosteroids
Immunomodulators
• Currently, only three anti-
TNFs are indicated for UC:
BIOLOGIC- Anti-TNF
INFLIXIMAB/ADALIMUMAB
NAIVE (INFLIXIMAB / ADALIMUMAB / GOLIMUMAB)
/ GOLIMUMAB
• VEDOLIZUMAB is indicated
Anti-integrin for both bio-naïve and bio-
(VEDOLIZUMAB)
experienced UC patients
• Potential Q8W to Q4W dose
Anti-TNF escalation for patients with
(INFLIXIMAB / ADALIMUMAB / GOLIMUMAB) decreased response to
VEDOLIZUMAB
BIOLOGIC- Anti-integrin
EXPERIENCED (VEDOLIZUMAB)
SurgeryMultiple pipeline and biosimilar products are pursuing UC in
the EU.
2018 2019 2020 2021
Infliximab
(Anti-TNF) SHP647
Anti-MAdCAM (mAb)
LAUNCH: 2018-2019
ETROLIZUMAB
Adalimumab
BIOLOGICS
[SC]
(Anti-TNF) (β7-integrin)
UC LAUNCH: DEC 2019
Golimumab
(Anti-TNF)
Vedolizumab
(Anti-integrin)
Tofacitinib (JAK Apremilast
ORAL SMALL
MOLECULES
inhibitor) (oral)
UC LAUNCH: (PDE4 inhibitor)
2018+ UC LAUNCH: ~2019-2020+
OZANIMOD(oral)
(S1P agonist)
UC LAUNCH: DEC 2019
BIOSIMILARS*
BIOSIMILAR BIOSIMILAR
INFLIXIMAB [SC] INFLIXIMAB
(Anti-TNF) (Anti-TNF)
BIOSIMILAR BIOSIMILAR
ADALIMUMAB ADALIMUMAB
[SC] (Anti-TNF)
(Anti-TNF)ASMR ASMR + ASMR +
Cost − Cost+
Decision
+ x B
C x
analysis
x C’
D A E
0 ASMR = 0 ASMR = 0
Cost − F x Cost +
x F’
REEVALUATION
- ASMR −
Cost −
ASMR −
Cost +
- 0
+ CostMaladie
Population traitée
Population
à traiter
Population
remboursable
ECR
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